A model of dopamine and serotonin-kynurenine metabolism in cortisolemia: Implications for depression

Abstract

A major factor contributing to the etiology of depression is a neurochemical imbalance of the dopaminergic and serotonergic systems, which is caused by persistently high levels of circulating stress hormones. Here, a computational model is proposed to investigate the interplay between dopaminergic and serotonergic-kynurenine metabolism under cortisolemia and its consequences for the onset of depression. The model was formulated as a set of nonlinear ordinary differential equations represented with power-law functions. Parameter values were obtained from experimental data reported in the literature, biological databases, and other general information, and subsequently fine-tuned through optimization. Model simulations predict that changes in the kynurenine pathway, caused by elevated levels of cortisol, can increase the risk of neurotoxicity and lead to increased levels of 3,4-dihydroxyphenylaceltahyde (DOPAL) and 5-hydroxyindoleacetaldehyde (5-HIAL). These aldehydes contribute to alpha-synuclein aggregation and may cause mitochondrial fragmentation. Further model analysis demonstrated that the inhibition of both serotonin transport and kynurenine-3-monooxygenase decreased the levels of DOPAL and 5-HIAL and the neurotoxic risk often associated with depression. The mathematical model was also able to predict a novel role of the dopamine and serotonin metabolites DOPAL and 5-HIAL in the ethiology of depression, which is facilitated through increased cortisol levels. Finally, the model analysis suggests treatment with a combination of inhibitors of serotonin transport and kynurenine-3-monooxygenase as a potentially effective pharmacological strategy to revert the slow-down in monoamine neurotransmission that is often triggered by inflammation.

Fig 1. Conceptual, simplified model of pathways associated with MDD and their interactions in the presynaptic DA and 5-HT terminals.

The model accounts for separate cytosolic and vesicular compartments in the two terminals, which share the same extracellular space. The latter is an important “collective” location for processes that take place outside the neurons, in particular, in the synaptic cleft or in glial cells. Metabolites are represented with white boxes and participating enzymes with black ellipses. Metabolites in dashed boxes are important but not necessarily located in the compartment where they are represented. Prefixes s, c, v, e, and p refer to metabolites in the serum, cytosol, vesicles, extracellular space and pool of proteins, respectively. Cortisol/corticosterone (CORT) is represented by a white diamond. Serum tyrosine, phenylalanine, tryptophan, enzymes and CORT are independent variables that remain constant during a given experiment. The strongest inhibitory effects are represented with dotted lines. Abbreviations: 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HIAL, 5-hydroxyindoleacetaldehyde; 5-HT, 5-hydroxytryptamine or serotonin; 5-HTP, 5-hydroxytryptophan; AADC, l-amino acid decarboxylase; ALDH, aldehyde dehydrogenase; COMT, catechol O-methyltransferase; DA, dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; HVA, homovanillic acid; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KP, kynurenine pathway; KYN, kynurenine; KYNA, kynurenic acid; KYNU, kynureninase; LAT, L-type amino acid transporter; L-DOPA, l-3,4-hydroxyphenylalanine; MAO, monoamine oxidase; PHE, phenylalanine; QPRT, quinolinate phosphoribosyltransferase; QUIN, quinolinic acid; SERT, serotonin transporter; TDO, tryptophan-2,3-dioxygenase; TH, tyrosine hydroxylase; TPH2, tryptophan hydroxylase 2; TRP, tryptophan; TYR, tyrosine; VMAT2, vesicular monoamine transporter 2.

Fig 2. New steady-state values of dependent variables in response to a 50% increase in CORT.

The percent changes were calculated in comparison to the corresponding values under control conditions (CORT at baseline of 100%). Also shown are the ratios QUIN/KYNA and KYNA/3-HK, which reflect the balance between levels of key metabolites.

Fig 3. Notable changes in key dependent variables in response to cortisolemia and treatment.

(A) Two-fold increase in the activity of VMAT2. (B) 95% Inhibition of the transporter SERT. (C) 50% Inhibition of the activity of enzyme KMO. (D) Combined inhibition of SERT (↓95%) and KMO (↓50%). Time courses are shown on the left and percent changes after treatment on the right of each panel. CORT is increased by 50% at day 8 and “treatment” starts at day 25 (black triangles).